Argatroban is an inhibitor of thrombin, the protease that plays a key role in the blood coagulation and fibrinolysis. (Stassen, J. M.; Arnout, J.; Deckmyn, H. Curr. Med. Chem., 2004, 11, 2245-2260. Sanderson, P. E. J.; NaylorOlsen, A. M. Curr. Med. Chem., 1998, 5, 289-304. Steinmetzer, T.; Sturzebecher, J. Curr. Med. Chem., 2004, 11, 2297-2321). The crucial role of thrombin in the coagulation cascade has made it a target for antithrombotic agents used in treatment of cardiovascular diseases (Abbenante, G.; Fairlie, D. P. Med. Chem. 2005, 1, 71-104). The most frequently prescribed anticoagulant with antithrombin activity is heparin, however limitations due to its chemical heterogeneity, in addition to several adverse events, as the heparin induced thrombocytopenia (HIT), prompted the development of low molecular weight selective inhibitors of thrombin. Argatroban (1; scheme 1) is a synthetic, small molecule that selectively and reversibly inhibits thrombin without generation of antibodies or degradation of proteases. (Yeh, R. W.; Jang, I K-K. Am. Heart J. 2006, 151, 1131-1138).

After identification by Okamoto and co-worker (U.S. Pat. No. 4,258,192, Mitsubishi 1979) argatroban was introduced in Japan (Novastan®, MD-805), and later in Europe and in US for prophylaxis and treatment of thrombosis in patients with HIT (Moledina, M.; Chakir, M.; Gandhi, P. J. J. Thrombosis and Thrombolysis 2001, 12, 141-149). Three constituents are easily recognized in the chemical structure 1, the 4-methyl-2-piperidine carboxylic acid bonded to the arginine, in turn bonded to a 3-methyl-1,2,3,4-tetrahydroquinoline through a sulfonyl group. Four stereogenic centers are present in the structure three of which, with a mandatory configuration, introduced either with the aid of a chiral auxiliary and by the use of L-arginine among the starting materials. The stereocenter on the tetrahydroquinoline is introduced during the last step of the synthesis by reduction of the heteroaromatic ring of a quinoline that affords the (21R)- and (21S)-diastereoisomers (Cossy, J.; Belotti, D. Bioorg. Med. Chem. Lett. 2001, 11, 1989-1992).
The diastereoisomeric mixture is used as antithrombotic drug without separation of the (21R)- and (21S)-epimers (Scheme 1), 1a and 1b, respectively, provided that their ratio is 64/36±2. The 21R and 21S configurations have been assigned in 1993 by a X-ray study after the HPLC separation. (21S)-1b is twice as potent as (21R)-1a and about five times less soluble in water (Rawson, T. E.; VanGorp, K. A.; Yang, J.; Kogan, T. P. J. Pharm. Sci. 1993, 82, 672-673).
In order to characterize from a chemical physical point of view the two 21-epimers of argatroban 1 the present Inventor tried their separation by means of a fractional crystallization according to a published procedure (CN 100586946) but the obtained results were unsatisfactory from a preparative point of view.
Therefore, alternative methods for the preparation of enantiomerically pure (R)- and (S)-isomers of 3-methyl-1,2,3,4-tetrahydroquinoline (2), i.e. the suitable synthons for the preparation of (21R)- and (21S)-argatroban 1 (Scheme 2), are still needed.

Two synthesis of optically active 3-methyl-1,2,3,4-tetrahydroquinoline 2, both aimed at the preparation of argatroban 1 or its analogues are reported in literature: in one case the starting material is a tricyclic chiral auxiliary that, after acylation, in five steps leads to the optically pure (3R)-methyl-6-bromo-1,2,3,4-tetrahydroquinoline (Brundish, D.; Bull, A.; Donovan, V.; Fullerton, J. D.; Garman, S. M.; Hayler, J. F.; Janus, D.; Kane, P. D.; McDonnel, M.; Smith, G. P.; Wakeford, R.; Walker, C. V.; Howarth, G.; Hoyle, W.; Allen, M. C.; Ambler, J.; Butler, K.; Talbot, M. D. J. Med. Chem. 1999, 42, 4584-4603). The synthesis of (3S)-methyl-1,2,3,4-tetrahydroquinoline is described in a Synthelabo's patent: the starting material, in this case, is the optically pure methyl (R)-3-iodo-2-methyl-propanoate (Lasalle, G.; Galtier, D.; Galli, F. 1995, U.S. Pat. No. 5,476,942). This synthesis presents very low overall yields.
However, a method for the preparation of both pure (3R)- and (3S)-methyl-1,2,3,4-tetrahydroquinoline starting from a common precursor and using the same reactant is not yet available.
An alternative method could be represented by a stereoselective catalytic hydrogenation of the suitable quinoline ring but it is reported that a chiral rhodium complex, giving optimal results (98% ee and quantitative yield) in the case of 2-substituted quinolines, failed the scope when applied to the 3-methylquinoline (Zhou, H.; Li, Z.; Wang, Z.; Wang, T.; Xu, L.; He, Y.; Fan, Q.-H; Pan, J.; Gu, L.; Chan, A. S. C. Angew. Chem. Int. Ed. 2008, 47, 8464-8467).
It has now been found an enzymatic approach for the synthesis of both enantiomerically pure (3R)- and (3S)-methyl-1,2,3,4-tetrahydroquinoline (compound 2).